title: The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition.
abstract: We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration of the spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.
authors.affiliation: Division of Hematology & Medical Oncology.
authors.forename: Angela G
authors.initials: AG
authors.lastname: Fleischman
authors.forename: Julia E
authors.initials: JE
authors.lastname: Maxson
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Luty
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.forename: Lacey R
authors.initials: LR
authors.lastname: Royer
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Abel
authors.forename: Jason D
authors.initials: JD
authors.lastname: MacManiman
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D006098:Granulocytes / Q000473:pathology; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000188:drug therapy / Q000235:genetics; D015467:Leukemia, Neutrophilic, Chronic / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D009570:Nitriles; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*
chemical_list: C517047:CSF3R protein, human; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016184:Receptors, Colony-Stimulating Factor; C540383:ruxolitinib; D053612:Janus Kinases